Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to bi-hetereoaryl compounds that inhibit the Vps34 enzyme and uses thereof for the treatment of diseases associated with such inhibition.
• the present invention includes bi-heteroaryl compounds, compositions thereof, methods of their use, and methods of their manufacture, where such compounds are generally pharmacologically useful in therapies whose mechanism of action rely on the inhibition of Vps34, and more particularly in therapies for the treatment of proliferative diseases, including cancer.
• Phosphoinositide 3-kinases are enzymes that phosphorylate the 3- hydroxyl position of the inositol ring of phosphoinositides ("Pis”), and are involved in diverse cellular events such as cell migration, cell proliferation, oncogenic
• Vps34 (vacuolar protein sorting 34") encodes a PI 3-kinase gene product that mediates the active diversion of proteins from the secretory pathway to vacuoles; mammals have a corresponding family of PI3-kinases, including three classes of PI3Ks, with a variety of isoforms and types within.
• the closest human homolog of yeast Vps34 is an 887 residue protein called PI3Kclass3 (“PI3KC3”)(also referred to herein as "hVps34,” for human Vps34), which shares about 37% sequence identity with the yeast protein over its full length (Volinia et al.
• hVps34 is the enzymatic component of a multiprotein complex that includes a ser/thr kinase called Vpsl5p, and proautophagic tumor suppressors Beclinl/Atg6, and UVRAG, and Bif-1 in mammals (Vpsl5, Atg6, and Atg 14 in yeast)(Mari et al. (2007) Cell Biol. 9: 1 125).
• Vpsl5p ser/thr kinase
• proautophagic tumor suppressors Beclinl/Atg6, and UVRAG and Bif-1 in mammals
• Vpsl5, Atg6, and Atg 14 in yeast Mari et al. (2007) Cell Biol. 9: 1 125.
• Vps34p The Vps34 gene product (Vps34p) is an enzyme required for protein sorting to the lysosome-like vacuole of the yeast, and appears to regulate intracellular protein trafficking decisions.
• Vps34p shares significant sequence similarity with the catalytic subunit of bovine phosphatidylinositol (PI) 3-kinase (the pi 10 subunit), which is known to interact with activated cell surface receptor tyrosine kinases.
• PI bovine phosphatidylinositol
• Vps34p Yeast strains deleted for the Vps34 gene or carrying Vps34 point mutations lacked detectable PI 3-kinase activity and exhibited severe defects in vacuolar protein sorting. Overexpression of Vps34p resulted in an increase in PI 3-kinase activity, and this activity was specifically precipitated with antisera to Vps34p (Schu et al. (1993) Science 260 (5104): 88).
• hVps34 is an integral part of the autophagy process, or eukaryotic cell mechanism for cytoplasmic renewal.
• Autophagy is a cellular catabolic degradation response to starvation or stress whereby cellular proteins, organelles, and cytoplasm are engulfed, digested, and recycled to sustain cellular metabolism.
• Autophagy is characterized by the engulfment of cytoplasmic material into specialized double-membrane vesicles known as autophagosomes. The degradation of cellular cytoplasmic components helps eukaryotic cells jettison defective organelles and protein complexes (Yorimitsu et al (2005) Cell Death Differ. 12: 1542).
• Nonselective autophagy can be initiated by starvation, allowing cells to convert organelles and proteins into nutrients for survival. Autophagy can also be employed to kill cells, in addition to or instead of apoptosis, for instance (Neufeld et al (2008) Autophagy).
• PI3K signaling can be attenuated by the
• phosphatase activity of the tumor suppressor PTEN phosphatase and tensin homologue detected in chromosome 10
• PTEN phosphatase and tensin homologue detected in chromosome 10.
• Inhibiting PI3K arrests a major cancer cell survival signaling pathway and overcomes the absence of tumor suppressor PTEN, providing antitumor activity and increased tumor sensitivity to a wide variety of drugs (Stein et al. (2001) Endocrine-Related Cancer 8:237).
• R 1 is Ci_ 6 alkyl, NR 3 R 6 , Ci_ 6 alkoxy, or -S-Ci_ 6 alkyl;
• R is Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, a C 6 -i 4 aryl group, a C3_i 4 cycloalkyl group, a 5 to -14 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from
• Ci-6alkoxy C 2 -6-alkenyloxy, C 2 -6-alkynyloxy, Ci_6alkyl-0-R , Ci_6alkyl-C3_ 14 cycloalkyl, Ci_ 6 alkyl-0-Co- 6 alkyl-C 6 -i 4 aryl, Ci_ 6 alkyl-0-SiR 8 R 9 R 10 , halogen, or d_ 6haloalkyl, wherein R 2 may be unsubstituted or substituted with OH, Cl-6alkoxy, or halogen;
• R and R are each independently H, Ci_ 6 alkyl, C2- 6 alkenyl, C 2 - 6 alkynyl, C 6 -i 4 aryl, C 3 _ i 4 cycloalkyl, a 3 to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms each independently selected from , O, and S, a 5 to -14 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from , O, and S, Ci_6alkoxy, OH, Ci_ 6 alkylNR n R 12 , Ci_ 6 alkyl-0-R 13 , Ci_ 6 alkyl-5 to 14-membered heteroaryl containing 1 to 3 heteroatoms each independently selected from , O, and S, or C(0)-Ci_ 6 alkyl, wherein said Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -i 4 aryl group, C 3 _
• R 3 and R 6 are independently H, Ci- 6 alkyl, Ci_ 6 alkyl-C 6 -i 4 aryl, Ci_ 6 alkoxy, a C 3 _ i 4 cycloalkyl, a 3- to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms each independently selected from O, N and S, a C 6 -i 4 aryl, a 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N, or S, or Ci_ 6 alkyl- O-R 8 , wherein Ci_ 6 alkyl, Ci_ 6 alkyl- C 6 -i 4 aryl, C ⁇ alkoxy, a C 3 _i 4 cycloalkyl group, a 3- to 14-membered cycloheteroalkyl group, a C 6 -i 4 aryl group, a 5- to 14-membered heteroaryl group, or -Ci_6alkyl
• R 11 and R 1"2 are each independently hydrogen, Ci_ 6 alkyl, C 3 _ 8 cycloalkyl, C 6 -i 4 aryl, 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N or S, 3- to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms each independently selected from O, N, or S, or NR n
• R 12 forms a non-aromatic four to seven membered ring optionally containing a second heteroatom selected from O, N and S, and optionally substituted by one or more substituents R 28 (preferably mono or
• R' and R 1 are independently H, Ci_ 6 alkyl, halogen, OH, or Ci_ 6 alkoxy. n is 0, 1, or 2; and
• R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28 are each independently H, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 3- tol4-membered cycloheteroalkylcontaining 1 to 3 heteroatoms selected from O, N or S, or a 5-to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N, or S.
• R 7 and R 7a are H or Ci_ 6 alkyl, such as methyl, ethyl, propyl, or butyl. In another embodiment, R 7 is H or methyl, and in yet another embodiment, R 7 is H. In an embodiment, n is 0 or 1. In another embodiment, n is 0.
• R 1 is Ci_ 6 alkyl, such as methyl, ethyl, or propyl; Ci_ 6 alkoxy, such as methoxy, or ethoxy; -S-Ci_ 6 alkyl, such as -SCH 3 , or -SCH 2 CH 3 , or -NR 3 R 6 , where R 3 and R 6 are independently H, or Ci_ 6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, or pentyl; Ci_ 6 alkyl-aryl, such as benzyl or ethyl-phenyl; Ci_ 6 alkoxy, such as methoxy or ethoxy; a C 3 _i 4 cycloalkyl group (e.g., cyclopropyl, cyclopentyl, or cyclohexyl); a 3- to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms selected from O,
• R 1 is methyl, ethyl, propyl, methoxy, ethoxy, methyl-phenyl, NH 2 , NH-(C 5 -alkyl)-OH, -NHCH 3 , -NH-CH 2 CH 2 (CH 3 ), -NHCH 2 CH(CH 3 ) 2 , -NH(C 4 - alkyl)-OH, or -NH(C 4 -alkyl).
• R 1 is NH 2 , -NH-(C 5 -alkyl)-OH, - NH(C 4 -alkyl), -NHCH 3 , or -NHCH 2 CH 2 (CH 3 ).
• one of R 3 or R 6 is H, and the other may be Ci_6alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl; Ci_6alkyl-aryl, such as benzyl, alpha-phenethyl, or beta-phenmethyl-phenyl; Ci_6alkoxy, such as methoxy or ethoxy; a C 3 _i4cycloalkyl, such as cyclopropyl, cyclopentyl, or cyclohexyl; a 3-14 membered cycloheteroalkyl, such as moprholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, or piperazinyl; a C 6 - i4aryl, such as phenyl; a 5-14 membered heteroaryl, such as pyridinyl, pyrazinyl, or pyrimi
• one of R 3 or R 6 is H, and the other is hydro xymethylene, hydroxyethylene (e.g., 1 -hydroxy ethyl or 2- hydroxy ethyl), hydroxypropyl (e.g., 1 -hydroxypropyl, 2-hydroxypropyl, 3- hydroxypropyl, or 1 -hydroxy- 1-methylethyl), hydroxybutyl (e.g., 1 -hydroxybutyl, 2- hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1 -hydroxy- 1 -methyl-propyl, 1 -hydroxy- 2,2-dimethyl-ethyl, or 2 -hydroxy- 1,1 -dimethyl-ethyl).
• both R and R 6 are H.
• R 2 is Ci_6alkyl, such as methyl, ethyl, propyl, or butyl; C 2 _ 6 alkenyl, ethenyl, propenyl; C 2 _6alkynyl, a C 6 -i4aryl group, such as phenyl; a C 3 _
• Mcycloalkyl group such as cyclopropyl, cyclopentyl, or cyclohexyl; Ci_6alkoxy, such methoxy, or ethoxy; C 2 -6-alkenyloxy, C 2 -6-alkynyloxy, -Ci_6alkyl-0-R 27 , where R 27 is H or Ci_ 6 alkyl (e.g., -CH 2 -0-CH 3 , or -CH 2 CH 2 -0-CH 3 , or CH 2 CH 2 -0-CH 2 CH 3 ); Ci_ 6 alkyl- C 3 _i4cycloalkyl (e.g., CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 - cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclobutyl, -CH 2 CH 2 -cycl
• R 2 is methyl, ethyl, propyl, ethenyl, propenyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, -CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 3 , - CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 - cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclobutyl, -CH 2 CH 2 -cyclopentyl, - CH 2 CH 2 -cyclohexyl, -CH 2 -0-CH 2 -phenyl, -CH 2 CH 2 -0-CH 2 -phenyl, -CH 2 -0-CH 2 CH 2 CH 2
• R 2 is methyl, ethyl, propyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, -CH 2 -O-CH 3 , -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 - cyclopentyl, -CH 2 -cyclohexyl, -CH 2 CH 2 -cyclopropyl, -CH 2 CH 2 -cyclobutyl, -CH 2 CH 2 - cyclopentyl, -CH 2 CH 2 -cyclohexyl, or -CH 2 -0-CH 2 -phenyl.
• R is methyl, ethyl, propyl, phenyl, cyclopropyl, methoxy, -CH 2 -O-CH 3 , -CH 2 - cyclopropyl, -CE ⁇ -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, or -CH 2 CH 2 - cyclopropyl.
• R is -CH 2 -cyclopropyl.
• R 4 and R 5 are each independently H, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, a C 6 -i 4 aryl, a C 3 _i 4 cycloalkyl, a 3- to 14-membered cycloheteroalkyl, a 5- to 14- membered heteroaryl group, Ci_ 6 alkoxy, OH, -Ci_ 6 alkylNR n R 12 , -Ci_ 6 alkyl-0-R 13 , Ci_ 6 alkyl-5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms each independently selected from O, N or S, or C(0)-Ci_ 6 alkyl, wherein R 4 or R 5 may be unsubstituted or substituted by substituents as iterated below.
• R 11 , R 12 , and R 13 are each independently H, Ci_ 6 alkyl, C 2 - 6 lkenyl, C 2 - 6 alkynyl, a C 6-14 aryl, a C 3-14 cycloalkyl group, a 3- to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms each independently selected from O, N or S, or a 5-14 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, or S.
• the present invention includes compounds of Formula (I) where R 4 and R 5 are each independently H, a C 6 -i 4 aryl, C3_i 4 cycloalkyl, a 3- to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms each independently selected from O, N or S, or a 5-14 membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N or S, wherein said C 6 -i 4 aryl, C3_i 4 cycloalkyl, 3 - to 14-membered cycloheteroalkyl, or 5- to 14-membered heteroaryl is optionally mono- or di-substituted by substituents selected from the group consisting of halogen, OH, Ci_ 6 alkyl, Ci_ ehaloalkyl, -Ci_ 6 alkylOH, Ci_ 6 alkoxy, -NR 14 R 15 , -C(0)ONR 16 R 17 ,
• R 4 is H
• R 5 is methyl, ethyl, propyl, phenyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, or pyridazinyl; each of which may be unsubstituted or substituted with one or more of halogen, a 5- to 14 membered heteroaryl (preferably, pyridinyl); OH, Ci_ 6 alkyl (preferably Cl-4alkyl; Ci_6haloalkyl (preferably, trifluoromethyl), Ci_6alkylOR 27 , Ci_ ealkoxy (preferably,methoxy, or ethoxy), -NR 14 R 15 , -C(0)NR 16 R 17 , -NR 18 C(0)R 19 , - NR 20 C(O)OR 21 , -C(0)R 22
• R 23 , R 24 , R 25 , R 26 , and R 27 are each independently H, Ci_ 6 alkyl (preferably, C ⁇ alkyl), C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, a C 6 -i 4 aryl (preferably, phenyl) C 3 _i 4 cycloalkyl (preferably, cyclopropyl, cyclopentyl, or cyclohexyl) 3- to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms each independently selected from O, N or S, or 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms each independently selected from O, N or S.
• Ci_ 6 alkyl preferably, C ⁇ alkyl
• C 2 _ 6 alkenyl C 2 _ 6 alkynyl
• a C 6 -i 4 aryl preferably, phenyl
• C 3 _i 4 cycloalkyl preferably,
• one of R 4 or R 5 is H, and the other is a moiety selected from methyl, ethyl, propyl, phenyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, or pyridazinyl; wherein said moiety is optionally with one to two substitutents each independently selected from the group consisting of F, CI, pyridinyl, OH, methyl, ethyl, trifluoro methyl, 1 -hydroxy ethyl, 2-hydroxyethyl, -C(0)OH, -NHC(0)0-isopropyl, -NH 2 , -NHS0 2 CH 3 , -S0 2 CH 3 , -CN, or -NHC(0)CH 3 .
• R 4 is H
• R 5 is methyl, ethyl, phenyl, or piperidinyl, wherein said methyl, said ethyl, said phenyl and said piperidinyl groups are optionally substituted with one or more substitutents each independently selected from - OH, -CN, CI, or F.
• one of R 4 and R 5 is H, and the other is phenyl or pyridinyl, wherein said phenyl and said pyridinyl are optionally substituted with one or more substitutents selected from F, CI, OH, methyl, ethyl, CN, or CF 3 .
• the present invention includes compounds of Formula II:
• R 1 is (Ci-C 6 )alkyl, -OCH 3 , -NH 2 , -NH(Ci-C 6 )alkyl, -NHCH 2 (phenyl),
• R 2 is (Ci-C 6 )alkyl, -CF 3 , -CH 2 (cyclopropyl), -CH 2 OH, or -CH 2 OCH 2 (phenyl); R 4 is H; and
• R 5 is (i). In anotehr embodiment -(CH 2 ) n -R 5a wherein n is 0 or 1. In another embodiment n is 0.
• R 5 is (ii).
• the present invention includes a method of inhibiting Vps34 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I) or its prodrug or pharmaceutical composition comprising the compound of formula I or its prodrug and pharmaceutically acceptable excipients to a subject in need thereof.
• disease, disorder, or syndrome is hyperproliferative in a subject, wherein said subject is an animal including humans, and the disease or disorder is selected from a group comprising cancer and inflammation.
• the present invention includes the compound of formula (I) for use in therapy.
• the present invention includes a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or excipient.
• the present invention includes a pharmaceutical composition comprising a compound of formula I in combination with a second active agent, and a pharmaceuticallyacceptable carrier or excipient.
• the present invention includes a method of treating a mammal comprising administration of a Vps34 inhibitor.
• the invention includes administration of a Vps34 inhibitor, where the Vps34 inhibitor is a compound of formula I.
• the compound is a stereoisomer or a tautomer.
• Representative compounds of the invention include:
• alkyl or “alkylene” refers to a straight chain or branched hydrocarbon from 1 to 20 carbon atoms. Alkyl moieties having from 1 to 5 carbons are referred to as "lower alkyl” and examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-pentyl, iso-pentyl, neopentyl and .
• Ci-6-halo alkyl refers to an alkyl group substituted by up to seven halogen groups, e.g. fluoro groups.
• halogen groups e.g. fluoro groups
• common haloalkyl groups are trifluoroalkyl, 2, 2, 2-trifluoroethyl or 2, 2, 2, 1, 1 -pentafluoroethyl groups.
• alkenyl refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon double bond.
• C2-C6-alkenyl refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon double bond.
• alkynyl refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond.
• C2-C6-alkynyl refers to a monovalent group derived from a hydrocarbon having two to six carbon atoms and comprising at least one carbon-carbon triple bond.
• alkoxy refers to a group in which an alkyl group is attached to oxygen, wherein alkyl is as previously defined.
• Cycloalkyl or “cycloalkylene” refers to a 3-14 membered monocyclic or bicyclic carbocyclic ring,
• the cycloalkyl may be attached using any of the ring members.
• Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• Aryl or “arylene” represents a 6-14 membered single or fused ring system, wherein at least one of the fused rings is aromatic and the other ring is another aromatic ring or a saturated or partially unsaturated cycloalkyl.
• the aryl may be attached using any of the ring members. Suitable aryl groups include phenyl, naphthyl, anthracyl and phenanthryl.
• Heteroaryl refers to a 5-14 membered monocyclic or fused ring system, wherein the monocyclic and at least one of the bicyclic fused rings is an aromatic ring comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, and the fused ring may be an aryl group, another heteroaryl, a saturated or partially unsaturated cycloalkyl, or a saturated or partially unsaturated hetero cycle.
• the heteroaryl may optionally include one to three ring members selected from the group consisting of -C(O), -N(R 31 )q-, -O- and S(0)r where R 31 is H or Ci-6-alkyl, q is 0-1 and r is 0-2.
• the heteroaryl may be attached using any of the ring members.
• Suitable monocyclic heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
• Suitable fused heteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, and quinolinyl
• Cycloheteroalkyl or “cycloheteroalkylene” or “heterocycle” refers to a 3-14 membered nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring comprising one or two ring members selected from the group consisting of-N(R 32 )-, -O- and -S(0) r -.
• the cycloheteroalkyl may be attached using any of the ring members.
• Suitable heterocycloalkyl groups include [1 , 3] dioxolane, [1, 4] dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, thiomorpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.
• Halogen or "halo” may be fluorine, chlorine, bromine or iodine.
• terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
• animal refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
• companion animals e.g., dogs, cats and horses
• food-source animals e.g., zoo animals, marine animals, birds and other similar animal species.
• Edible animals refers to food-source animals such as cows, pigs, sheep and poultry.
• phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
• the terms “treating”, “treat”, or “treatment” embrace both preventative, i.e., prophylactic, and palliative treatment.
• compounds of the present invention refer to compounds of Formula (I), prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds.
• the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by the inhibition of Vps34.
• Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
• the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
• reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
• Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
• Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds.
• specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
• many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
• step 1 involves the alkylation of commercially available 4-methyl-2-(methylthio)pyrimidine with R2 substituted Weinreb amides, or alternatively R2-substituted benzyl esters. Further reaction of ketones of formula 2 with ⁇ , ⁇ -dimethylformamide dimethyl acetal in the absence of solvent at 80 °C affords vinylogous amides 3.
• Intermediates of the formula 4a-f are prepared by cyclization of intermediate 3 with R-substituted guani dines at 120 °C in the presence of a base such as potassium carbonate.
• step 4 the sulfide is converted to the sulfoxide or sulfone by reaction with a suitable oxidizing agent, such as m- Chloroperoxybenzoic acid.
• a suitable oxidizing agent such as m- Chloroperoxybenzoic acid.
• Conversion to final compounds I-A can be accomplished by reaction of intermediates 5 with aliphatic amines in the microwave at 160 °C or by addition of deprotonated aryl or heteroarylamines.
• step 1 involves the oxidation of the sulfide to the sulfone or sulfoxide utilizing a suitable oxidizing agent such as m-Chloroperoxybenzoic acid.
• a suitable oxidizing agent such as m-Chloroperoxybenzoic acid.
• the sulfoxide or sulfone moiety can then be displaced by reaction with aliphatic amines in the microwave at 160 °C or alternatively by addition of deprotonated aryl or heteroarylamines.
• Further reaction of ketones of formula 8 with N,N-dimethylformamide dimethyl acetal in the absence of solvent at 80 °C affords vinylogous amides 9.
• Compounds II-A can be prepared from intermediate 9 via reaction with 2-methyl-2- thiopseudourea sulfate in the presence of a suitable base such as potassium carbonate at 120 °C followed by reaction of intermediate 11 with R substituted amines in the microwave at 160 °C.
• a suitable base such as potassium carbonate at 120 °C
• Compounds I-A can be prepared from intermediate 9 by heating with R substituted guani dines.
• the compounds of formula III-A can be prepared according to Scheme 3, starting from 5-acetyl-2-amino-4-methylpyrimidine (Alfa Aesar) and heating in N,N- dimethylformamide dimethyl acetal, followed by reaction with substituted guanidines in the presence of a suitable base such as potassium carbonate at 120 °C.
• a suitable base such as potassium carbonate at 120 °C.
• the compounds of formula 1 V-A can be prepared according to scheme 4, utilizing a Suzuki coupling with the appropriate boronate ester and 2,4- dichloropyrimidine. Subsequent reaction with various amines in the microwave affords the desired aminopyrimidines.
• Scheme V Generally, the compounds of formula V-A can be prepared according to Scheme 5, starting from 5-acetyl-2-thioxo-2,3-dihydropyrimidin-4(lH)-one (Ryan Scientific). Step 1 involves methylation, which is followed by reaction with N,N-dimethylformamide dimethyl acetal at 120 °C and subsequent reaction with substituted guanidines in the presence of a suitable base such as potassium carbonate at 120 °C. Final compounds are prepared by chlorination with a reagent such as POCI 3 followed by reaction with various amines at 200 °C in the microwave.
• a reagent such as POCI 3
• the compounds of the present invention may be isolated and used per se or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate. Many of the compounds represented by Formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
• Pharmaceutically acceptable acid addition salts of the compound of the present invention include those of inorganic acids, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, , propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxy
• compositions of the present invention which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of Formula I by known salt-forming procedures. For those compounds containing an asymmetric carbon atom, the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
• the present invention embraces both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof.
• the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
• Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid
• enantiomers may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a commercially available chiral HPLC column.
• solvates are considered pharmaceutical compositions, e.g., a compound of Formula I (or pharmaceutically acceptable salt thereof) in combination with an excipient, wherein the excipient is a solvent.
• tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
• proton tautomers also known as prototropic tautomers
• proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
• a specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens.
• Valence tautomers include interconversions by reorganization of some of the bonding electrons.
• the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such
• substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
• Compounds of the present invention are useful for treating diseases, conditions and disorders modulated by the inhibition of the Vps34 enzyme; consequently, the compounds of the present invention (including the compositions and processes used therein) may be used in the manufacture of a medicament for the therapeutic applications described herein.
• another embodiment of the present invention is a
• composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
• a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
• Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
• the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied.
• Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
• safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
• Suitable aqueous solvents include water, ethanol, propylene glycol,
• polyethylene glycols e.g., PEG400, PEG300, etc. and mixtures thereof.
• formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• the formulations may be prepared using conventional dissolution and mixing procedures.
• the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
• a suitable solvent in the presence of one or more of the excipients.
• the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
• the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
• an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
• Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
• the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
• the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
• the compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of VPS34, as well as diseases or conditions modulated by the autophagy and endocytic pathways.
• Vps34 inhibitors can be used to inhibit autophagy in a variety of diseases, including but not limited to a variety of human cancers including colon/rectum, lung, breast, prostrate, urinary, kidney, and pancreatic.
• diseases where Vps34 can be used to modulate autophagy include neurodegenerative disorders such as HD, PD, ALS, inflammatory bowel disease (including Crohn's disease), malarial infection, and dengue.
• the invention relates to a method for treating a disease or condition related to the hyperactivity of Vps34, or a disease or condition modulated by the Vps34, comprising administration of an effective therapeutic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention relates to a method for treating proliferative diseases, such as cancer, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• cancers include but are not limited to acute and chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non- Hodgkin's lymphoma, malignant lymphoma, colorectal cancer, kidney, lung, liver, pancreatic, breast, glioma, or neuroblastoma.
• compounds of formula (I) may also be useful as therapeutics for diseases such as muscle diseases such as central nuclear myopathies (e.g. X-linked myotubular myopathies), chloroquine-induced myopathy, myopathies with excessive autophagy, Duchene's muscular dystrophy, Charcot Marie Tooth Disease (e.g. type 4B),
• muscle diseases such as central nuclear myopathies (e.g. X-linked myotubular myopathies), chloroquine-induced myopathy, myopathies with excessive autophagy, Duchene's muscular dystrophy, Charcot Marie Tooth Disease (e.g. type 4B),
• An Vps34 inhibitor of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer.
• a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from, e.g., proteosome inhibitors, Bcl-2 inhibitors, Bcr-Abl inhibitors such as Gleevec and derivatives, mTOR inhibitors, PI3K inhibitors, dual PI3K-mTOR inhibitors, lipid kinase inhibitors, Ras, Raf, MEK, ERK1/2 inhibitors, TNF-R ligands, UPR ER stress inducers, or other chemo therapeutic compounds.
• DMARDs disease-modifying antirheumatic agents
• mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune), everolimus (CerticanO), CCI-779, RAD001 , and ABT578.
• mTOR inhibitors would include "catalytic" modulators such as NVP-BEZ235 and Ku- 0063794.
• proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
• Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (Velcade) and MLN 341.
• the term “compounds targeting/decreasing a protein or lipid kinase activity”; or a “protein or lipid phosphatase activity”; or “further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
• PDGFR platelet-derived growth factor-receptors
• FGFR fibroblast growth factor-receptors
• IGF-IR insulin-like growth factor receptor I
• compounds which target, decrease or inhibit the activity of IGF-IR especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors;
• kits/SCFR receptor tyrosine kinase i.e C-kit receptor tyrosine kinases - (part of the PDGFR family)
• compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family especially compounds which inhibit the c-Kit receptor, e.g. imatinib
• h compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g.
• BCR-Abl kinase and mutants, such as corn-pounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825)
• a N-phenyl-2-pyrimidine-amine derivative e.g. imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825)
• UCN-01 safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; BEZ235 (a P13K inhibitor) or AT7519 (CDK inhibitor);
• tyrphostin is preferably a low molecular weight (mw ⁇ 1500) compound, or a
• a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- ⁇ [(2,5- dihydroxyphenyl)methyl] amino ⁇ -benzoic acid adamantyl ester; NSC 680410, adaphostin);
• k) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex.
• trastuzumab Herceptin
• cetuximab Erbitux
• Iressa Tarceva
• OSI-774 CI-1033
• EKB-569 GW-2016
• El .l E2.4, E2.5, E6.2, E6.4, E2.1 1, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541;
• compounds targeting, decreasing or inhibiting the activity of the c-Met receptor such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF.
• “Other chemotherapeutic compounds” include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
• LHMDS Lithium hexamethyldisilazide
• LiHMDS Lithium hexamethyldisilazide
• Method 1 Inertsil ODS3 100 x 3mm CI 8 column at the flow rate of 1.0 mL/min, with a gradient of 5-95% acetonitrile/water with 0.1% formic acid over 7.75 min.
• Method 2 Inertsil C8-3 column with a gradient of 5-95% acetonitrile/water with 5mM ammonium formate over 2.0 min.
• reaction was slowly warmed up to rt, then the reaction was allowed to stir for 1 hour.
• the reaction was quenched with saturated ammonium chloride solution, then concentrated in vacuo.
• the reaction was taken up in acetonitrile, purified by reverse-phase HPLC [10-90% organic phase over 15 minutes], then further purified by BiotageTM silica gel chromatography [lOg SNAP column, 100% DCM to 7%
• reaction was purified directly by reverse phase HPLC with a gradient of 10-90% acetonitrile in water over 15 minutes and then further purified by flash chromatography with a gradient of 25-100% ethyl acetate in heptane to give the desired product as a white solid (7.36 mg).
• reaction mixture was purified by a reverse- phase Gilson HPLC [30-90% organic phase over 15 min] followed by a Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a glassy solid (90 mg, 21% yield).
• MS (ES+): m/z 392.2/393.2/394.3 (100/40/10) [MH + ].
• HPLC: t R 1.12 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
• the crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by BiotageTM silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (19.76mg, 33%).
• the crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by BiotageTM silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (9.13mg, 16.3%).
• the crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by BiotageTM silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (23.9mg, 41%).
• bipyrimidine-2, 2 '-diamines 12a-c bipyrimidine-2, 2 '-diamines 12a-c.
• the reaction was quenched by slow addition of saturated ammonium chloride and the reaction mixture was diluted with EtOAc. The residue was then partitioned between water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo.
• the crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by BiotageTM silica gel chromatography [lOg SNAP column, 100% DCM to 10% MeOH/DCM] to obtain the desired product as a pale yellow solid (94 mg, 88% yield).
• the product was taken up in 10% MeOH/DCM, then was purified by BiotageTM silica gel chromatography [ 1 Og SNAP column, 2-10% MeOH/DCM] and further purified by trituration with acetone and acetonitrile to obtain the desired product as a pale yellow solid (10.23 mg, 18% yield).
• the reaction mixture was heated at 120°C for 48 hours. Additional 1 -(4-cyanophenyl)guanidine (2.076 g, 8.91 mmol) and K 2 C0 3 (3.69 g, 26.7 mmol) were added, and the reaction mixture was stirred at 120°C for additional 18 hours. The reaction mixture was cooled to rt, then was slowly poured into an ice-cooled IN HCl solution while stirring vigorously. The reaction mixture was neutralized with additional IN HCl, then the reaction mixture was allowed to stir for an additional 30 minutes. The resulting precipitate was filtered, washed multiple times with DI water, 2-propanol, then diethyl ether.
• Vps34 KinaseGlo assay 50 nL of compound dilutions were dispensed onto black 384- well low volume Non Binding Styrene (NBS) plates (Costar Cat. No. NBS#3676). L-a- phosphatidylinositol (PI), provided as 10 mg/mL solution in methanol (Avanti Polar Lipid; Cat. No. 840042C, Lot#LPI-274), was transferred into a glass tube and dried under nitrogen beam. It was then resuspended in 3% OctylGlucoside by vortexing and stored at 4°C. 5 ⁇ of a mix of PI/OG with recombinant human Vps34 were added.
• NBS Non Binding Styrene
• Kinase reactions were started by addition of 5 ⁇ of ATP-mix containing in a final volume 10 iL 10 mM TRIS-HCl pH 7.5, 3mM MgC12, 50 mM NaCl, 0.05% CHAPS, ImM DTT and 1 ⁇ ATP, and occured at room temperature. Reactions were stopped with 10 ⁇ of KinaseGlo and plates were read 10 minutess later in a Synergy2 reader using an integration time of 0.1 seconds per well.
• the luminescence-based ATP detection reagent KinaseGlo was obtained from Promega, (Cat.No. V6714, Lot No. 236161) through Catalys, Wallisellen, Switzerland.
• IC50 values of the percentage inhibition of each compound at 8 concentrations were derived by fitting a sigmoidal dose response curve to a plot of assay readout over inhibitor concentration.

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